Abstract

The fungus Paracoccidioides brasiliensis (Pb), causative agent of chronic systemic mycosis endemic in rural areas of Latin America, is sensed by the TLR-2, 4 and dectin-1 receptors. However, during this infection, the upstream pathways responsible for the cytokines production by macrophages as IL-1β and IL-18 are completely unknown. In Nlrp3-/- macrophages (BMMs), although amounts of IL-1β were reduced, it is still detectable when compared with uninfected macrophages, suggesting that there are additional receptors required for caspase-1 activation and IL-1β production. Then, we evaluate if Nlrc4 could induce IL-1β production and caspase-1 activation in vitro. Strikingly, we observed higher IL-1β release and caspase-1 activation in Nlrc4-/- BMMs than WT cells. To characterize the role of Nlrc4 during experimental infection, WT and Nlrc4-/- mice were infected intravenously with 1x10^6 yeasts forms of Pb18 and fungal burdens in the lung were analyzed at day 15 and 30 post infection. Whereas at 15 dpi WT and Nlrc4-/- mice had similar fungal counts in the lung tissue, at 30 dpi the lung homogenates from Nlrc4-/- mice contained lower numbers of Pb colony-forming units. Moreover, we showed that the reduction in number of viable yeasts was followed by compact and well defined granulomas formation. Taken together, these results suggest that Nlrc4 mediates efficient granulomatous organization and host resistance to P. brasiliensis infection. Financial support: FAPESP, CNPq, CAPES